The modern concept of the biorefinery is characterized by the production of fuels, commodity chemicals, and value-added products from non-petroleum based carbon sources (Clark and Deswarte (2015) In Introduction to Chemicals from Biomass, Second Edition. 1-29). There is a strong movement in the physical and biological sciences in support of the biorefinery concept, established around the proposition that the unabated use of all current fossil fuel reserves will have serious, potentially irreversible environmental consequences (McGlade and Ekins (2015) Nature 517: 187). The synthesis of value-added products (e.g., agrochemicals and healthcare products) from biomass feedstocks is a key strategy within this movement to leverage business models organized principally around low-margin, high-volume commodities such as biofuels and polymers.
Examples of such value-added products include healthcare products for individuals suffering from atherosclerosis. Atherosclerosis is a chronic inflammatory condition which is the primary cause of cardiovascular diseases that account for about half of the mortalities in developed countries (Lusis (2000) Nature 407: 233). Diets rich in fish and marine organisms are recognized to have an anti-atherosclerotic effect (Calder (2004) Clin. Sci. 107:1; Biscione et al. (2007) Curr. Vasc. Pharmacol. 5: 163; and von Schaky (2007) Curr. Opin. Clin. Nutr. Metab. Care 10:129). While the polyunsaturated omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are credited to be the active components of fish oil, furan fatty acids (FFAs) are now also believed to play a significant role (Vetter and Wendlinger (2013) Lipid Technol. 25: 7; and Spiteller (2005) Lipids 40:775). For example, it has been demonstrated that FFAs exhibit a greater anti-inflammatory effect than EPA in arthritis models (Wakimoto et al. (2011) Proc. Natl. Acad. Sci. 108: 17533). It has even been theorized that FFAs, rather than omega-3 acids, are responsible for the cardioprotective effects of fish consumption (Glass et al. (1975) Lipids 10: 695). Multiple in-vitro antioxidant studies of FFAs have demonstrated that the compounds suppress lipid peroxidation by scavenging radicals and singlet oxygen species (Ishii et al. (1989) Chem. Pharm. Bull. 37: 1396), suggesting applications in the management of hyperlipidemia (Tsuji and Wakimoto (2009) Jpn. Kokai Tokkyo Koho JP2009062315), autoimmune disorders (Tsuji and Wakimoto (2009) Jpn. Kokai Tokkyo Koho JP2009062314), and dermatitis (Tsuji and Wakimoto (2009) Jpn. Kokai Tokyo Koho JP2009062316). Recent studies also show that FFAs can effectively rescue brain cells from cell death induced by oxidative stress (Teixeira et al. (2013) Food Funct. 4: 1209), while other work has even pointed to potential anti-tumor activity (Isoda et al. (1993) J. Japan Oil Chem. Soc. 42: 923).
FFAs from marine sources were first isolated and structurally characterized in 1974 (Glass et al (1994) Lipids 9: 1004; and Glass et al. (1975)). All marine FFAs are typified by a long fatty acid chain at the 2-position of the furan ring and a C3 or C5 alkyl chain at the 5-position. One or both of the remaining positions of the ring (R1, R2) may be substituted with a methyl group. Due to their low natural abundance and sensitivity to isolation procedures, a number of synthetic approaches to these compounds have been reported. Since FFAs are biogenetically derived by the oxidation of lipids (Batna and Spiteller (1991) Liebigs Ann. Chem. 861; and Shirasaka et al. (1997) Biochim. Biophys. Acta 1346: 253), the most evident synthetic route would be via the corresponding unsaturated C16-C20 acids. Thus, Ellamar and co-workers submitted oleic acid to microbial oxidation with Pseudomonas aeruginosa PR3 to give 7,10-dihydroxy-8-octadecenoic acid, which could be thermally cyclized to an unnatural FFA (FIG. 1, 5, n=6, m=4, R1=R2=H), the antioxidant activity of which was low (Ellamar et al. (2011) J. Agric. Food Chem. 59: 8175). A simpler approach was reported by Yurawecz et al., who aerated a sample of linoleic acid at 50° C. over the course of several hours to give a mixture of FFAs, albeit with very low conversion (Yurawecz et al. (1995) Lipids 30: 595). Lie Ken Jie and Ahmad adapted a method for producing unmethylated FFAs via epoxidation of doubly unsaturated fatty acids (Gunstone and Schuler (1975) Chem. Phys. Lipids 15: 174) to generate a mixture of dimethyl FFAs in five steps via oxidation of methyl linoleate, again however in low overall yield (Lie Ken Jie and Ahmad (1981) J. Chem. Soc. Chem. Comm. 1110).
More efficient, total synthetic approaches to FFAs have also been described by various groups. The first reported synthesis of a natural furan fatty acid pre-dates their isolation from fish, instead referring to the observation of FFA (FIG. 1, 5 n=4, m=6, R1=R2=H) in the seeds of a sandalwood shrub (Morris et al. (1966) Tetrahedron Lett. 4249). The route encompasses five steps starting from furoic acid with a total yield of <10% (Elix and Sargent (1968) J. Chem. Soc. 595). Other efforts towards unmethylated FFAs include hydration of octadecadiynoate esters (Lie Ken Jie and Lam (1977) Chem. Phys. Lipids 19: 275), and multistep approaches via furan, furfural, and furfuryl alcohol (Lie Ken Jie and Lam (1978) Chem. Phys. Lipids 21: 275; and Buchta and Huhn (1965) Liebigs Ann. Chem. 686: 77).
The first total synthesis of the methylated FFAs was reported by Rahn and co-workers, and was 5-6 steps from the advanced starting materials 3,4-bis-(acetoxymethyl)furan and methyl 3-methyl-2-furoate (Rahn and Sand (1979) J. Org. Chem. 44: 3420). Marson and Harper employed an unconventional approach starting from cycloundecanone, which could be converted to 5 of FIG. 1 (n=3, m=9, R1=H, R2=Me) in 6 steps and 13% overall yield (Marson and Harper (1998) Tetrahedron Lett. 39: 333; and Marson and Harper (1998) J. Org. Chem. 63: 9223). A contribution by Bach and Kruger showcases a Pd(0)-catalyzed coupling between a 10-undecynoate ester and 4,5-dibromofurfural, followed by Wittig olefination, methylation with MeZnCI, and finally hydrogenation to 5 of FIG. 1 (n=3, m=9, R1=H, R2=Me) in 28% overall yield (Bach and Kruger (1998) Tetrahedron Lett. 39: 1729; and Back and Kruger (1999) Eur. J. Org. Chem. 2045). Finally, Knight et al. described syntheses of both monomethylated (n=3, m=9, R1=H, R2=Me) and dimethylated 5 of FIG. 1 (n=3, m=9, R1=R2=Me) starting from the mono-TBS derivative of 1,12-dodecanediol, which was converted into an alkyne diol precursor for Ag(I)-catalyzed cyclization to the furan products. The overall route involved 8-9 steps in 40 and 32% yields, respectively (Evans et al. (2008) ARKIVOC 95). A later optimization of this route starting from 10-undecenal provided the same FFAs in improved yields (63 and 48%, respectively) by employing gold(III) catalysis, among other minor variations (Knight and Smith (2012) Heterocycles 84: 361). All of the above syntheses suffer either from low yields or the use of expensive starting materials or reagents.
Previous work successfully accomplished the syntheses of the natural herbicide δ-aminolevulinic acid 2 of FIG. 1 (Mascal and Dutta (2011) Green Chem. 13: 40), the anti-ulcer drug ranitidine (Zantac) 3 of FIG. 1 (Mascal and Dutta (2011) Green Chem. 13: 3101), and the furan-based pyrethroid insecticide prothrin 4 of FIG. 1 (Chang et al. (2014) J. Agric. Food Chem. 62: 476) from the renewable platform molecule 5-(chloromethyl)furfural (CMF) 1 of FIG. 1, which can be derived in a single step from sugars, cellulose, or raw biomass in isolated yields as high as 80% (Mascal and Nikitin (2008) Angew. Chem. Int. Ed. 47: 7924; and Mascal and Nikitin (2009) ChemSusChem 2: 859). The present invention surprisingly meets the need for a high-yielding approach to naturally occurring and biologically active FFAs, as well as other needs, by demonstrating the additional synthesis of FFAs from this CMF platform.